The Non-hormonal Male Contraceptive Adjudin Exerts its Effects via MAPs and Signaling Proteins mTORC1/rpS6 and FAK-Y407.

Abstract

Adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (formerly called AF-2364), is a nonhormonal male contraceptive, since it effectively induces reversible male infertility without perturbing the serum concentrations of follicle stimulating hormone (FSH), testosterone, and inhibin B based on studies in rats and rabbits. Adjudin was shown to exert its effects preferentially by perturbing the testis-specific actin-rich adherens junction (AJ) at the Sertoli-spermatid interface known as apical ectoplasmic specialization (apical ES), thereby effectively inducing spermatid exfoliation. Adjudin did not perturb germ cell development nor germ cell function. Also, it had no effects on Sertoli cell-cell AJ called basal ectoplasmic specialization (basal ES), which, together with tight junction constitute the blood-testis barrier (BTB), unless an acute dose of adjudin was used. Adjudin also did not perturb the population of spermatogonial stem cells nor Sertoli cells in the testis. However, the downstream signaling protein(s) utilized by adjudin to induce transient male infertility remains unexplored. Herein, using adult rats treated with adjudin and monitored changes in the phenotypes across the seminiferous epithelium between 6 and 96 h in parallel with the steady-state protein levels of an array of signaling and cytoskeletal regulatory proteins, recently shown to be involved in apical ES, basal ES and BTB function. It was shown that adjudin exerts its contraceptive effects through changes in microtubule associated proteins (MAPs) and signaling proteins mTORC1/rpS6 and p-FAK-Y407. These findings are important to not only study adjudin-mediated male infertility but also the biology of spermatogenesis.

• Authors: Lingling Wang, Ming Yan, Huitao Li, Siwen Wu, Renshan Ge, Chris K C Wong, Bruno Silvestrini, Fei Sun, C Yan Cheng
• Journal: Endocrinology (Endocrinology) Vol. 162 Issue 1 (01 01 2021) ISSN: 1945-7170 [Electronic] United States
• PMID: 33094326 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• 1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide
• Hydrazines
• Indazoles
• Microtubule-Associated Proteins
• Ribosomal Protein S6
• Rps6 protein, rat
• Focal Adhesion Kinase 1
• Ptk2 protein, rat
• Mechanistic Target of Rapamycin Complex 1
• Cadmium Chloride

Topics

• Animals
• Cadmium Chloride (toxicity)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Hydrazines (pharmacology)
• Indazoles (pharmacology)
• Male
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• Microtubule-Associated Proteins (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Ribosomal Protein S6 (genetics, metabolism)
• Signal Transduction (drug effects, physiology)